Real-World Evidence (RWE):Context for Supporting Regulatory Decisions

Michael Waters, Ph.D.

SHIELD Team Lead/OIR RWE Representative

Office of In Vitro Diagnostics and Radiological Health (OIR)Center for Devices and Radiologic Health (CDRH)

Food and Drug Administration (FDA)

Systemic Harmonization and Interoperability Enhancement for Lab Data

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FDA Reauthorization Act (FDARA) including MDUFA IV commitment to use of real-world evidence to support device pre/postmarket decisions

National Evaluation System for health Technology (NEST)

CDRH Strategic Priorities

Guidance issued to clarify how RWE may be used to support regulatory decisions

Context for RWE Guidance

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Context for RWE Guidance

FDA Reauthorization Act (FDARA) including MDUFA IV commitment to use of real-world evidence to support device pre/postmarket decisions

National Evaluation System for health Technology (NEST)

CDRH Strategic Priorities

Guidance issued to clarify how RWE may be used to support regulatory decisions

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Turning Data into Evidence

Real-World Data (RWD)“Data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources”

Real-World Evidence (RWE)“Clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of RWD”

RWD RWEAnalysis

Guidance Addresses issues related processes of:• Generation and collection of RWD• Analysis of RWD• When results might be considered valid scientific evidence

Collection Use

Traditional and Real-World Evidence

Pre-Clinical Testing

Post-MarketPre-MarketApplication

Analysis Selection Data Generation

New HypothesesDevice Innovation

Informed Clinical Decision Making

ClaimsDatabases

LaboratoryTests

PharmacyData

PatientExperience

SocialMedia

Registries

Electronic Health

Records

HospitalVisits

HealthcareInformation

Real-World Data/Evidence

Clinical Studies

(IDE)

Design Conduct Analysis

Traditional Regulatory Pathway

Real-World Device UsePhysician and Patient

Experience

New HypothesesDevice Innovation

Informed Clinical Decision Making

Analysis Selection Data Generation

ClaimsDatabases

LaboratoryTests

PharmacyData

PatientExperience

SocialMedia

Registries

Electronic Health

Records

HospitalVisits

HealthcareInformation

Real-World Data/Evidence

Traditional and Real-World Evidence

Pre-Clinical Testing

Post-MarketPre-MarketApplication

Clinical Studies

(IDE)

Design Conduct Analysis

Traditional Regulatory Pathway

Real-World Device UsePhysician and Patient

Experience

DATA QUALITY NEEDED!

RWE must be understood and

reliable to be useful

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Valid Scientific Evidence

• 21CFR 860.7(c)(1)

– Although the manufacturer may submit any form of evidence to the Food and Drug Administration in an attempt to substantiate the safety and effectiveness of a device, the agency relies upon only valid scientific evidence to determine whether there is reasonable assurance that the device is safe and effective.

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What is Acceptable?

• 21 CFR 860.7(c)(2)Valid scientific evidence is evidence from– Well-controlled investigations,– Partially controlled studies, – Studies and objective trials without matched controls, – Well-documented case histories conducted by qualified

experts, – Reports of significant human experience with a

marketed device from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use.

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What is Not Acceptable?

• 21 CFR 860.7(c)(2) continued…Isolated case reports, random experience, reports lacking sufficient details to permit scientific evaluation, and unsubstantiated opinions are not regarded as valid scientific evidence to show safety or effectiveness. Such information may be considered, however, in identifying a device the safety and effectiveness of which is questionable.

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Data Quality

Benefit Risk

Safety…probable benefits to health

from use of the device outweigh any probable risks

[21 CFR 860.7(d)(1)]

Effectiveness…use of the device in the

target population will provide clinically significant results

[21 CFR 860.7(e)(1)]

‘Fit for Purpose’Data must be complete, consistent, accurate, and

contain all critical data elements needed to evaluate a medical device and its claims.

Relevant & Reliable

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• 21 CFR 812 Investigational Device Exemptions

• 21 CFR 50 Protection of Human Subjects(Informed Consent)

• 21 CFR 54 Financial Disclosure of Investigators

• 21 CFR 56 Institutional Review Boards (IRBs)

• 45 CFR 46 “Common Rule”

• Health Insurance Portability and Accountability Act (HIPAA)

• Other federal and local regulations

• RWE Guidance does not address all issues related to patient protection - focus is on the IDE process.

Patient Protections

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HIPAA Privacy Rule

Traditional Regulatory Pathway – 21 CFR 50, 54, 56, 812 Apply

Pre-Clinical Testing

Post-MarketPre-MarketApplication

Informed Clinical Decision Making

Real-World Device UsePhysician and Patient

Experience

New HypothesesDevice Innovation

Clinical Studies

(IDE)

ClaimsDatabases

LaboratoryTests

PharmacyData

PatientExperience

SocialMedia

Registries

Electronic Health

Records

HospitalVisits

Healthcare

Information

Patient Protections

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Research on Information

Pre-Clinical Testing

Post-MarketPre-MarketApplication

Informed Clinical Decision Making

New HypothesesDevice Innovation

Clinical Studies

(IDE)

ClaimsDatabases

LaboratoryTests

PharmacyData

PatientExperience

SocialMedia

Registries

Electronic Health

Records

HospitalVisits

Healthcare

Information

Real-World Device UsePhysician and Patient

Experience

Access and Use –Research Under Common Rule

21 CFR 50, 56

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RWE Example Case Studies# Device (Submission) Data Source Used Action

1 Wearable (PMA/S) Wearable Device & Patient Reports

Modification of claims from adjunctive to non-adjunctive to use diagnostic for treatment decisions

Indication Expansion

2 Computer assisted triage software (De Novo)

Literature Peer reviewed literature Meta-analysis.

NewIndications

3 Sequencing assay (510(k))

Public NGS database

Publicly-maintained database support clinical validity of the test in lieu of clinical trials

Indication Expansion

4 Screening assay (De Novo)

State lab & surveillancedatabases

Pivotal clinical trial was embedded in routine clinical practice (under an IDE) in lieu of a traditional pivotal trial.

NewIndications

5 Implantable Cardioverter-Defibrillator (PAS)

Multiple RWD data sources

Monitor multiple aspects of real-world device safety and performance using data collected in routine care.

Condition of Approval

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Case Example: Leveraging a RWD Database to Enable Pre-Market Claims

FDA cleared two 510(k)s for sequencing assays for variant/variant combinations associated with cystic fibrosis using a public next-generation sequencing (NGS) database.

Traditional Studies: Full clinical trials/summary of information available in peer-reviewed literature to provide evidence of the test’s clinical validity.

https://www.accessdata.fda.gov/cdrh_docs/reviews/K124006.pdfhttps://www.accessdata.fda.gov/cdrh_docs/reviews/K132750.pdf

https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm509837.pdf

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Case Example: Leveraging a RWD Database to Enable Pre-Market Claims

FDA cleared two 510(k)s for sequencing assays for variant/variant combinations associated with cystic fibrosis using a public next-generation sequencing (NGS) database.

Traditional Studies: Full clinical trials/summary of information available in peer-reviewed literature to provide evidence of the test’s clinical validity.

• Database used as a source of valid scientific evidence to establish which variants/ variant combinations were causal for the target disease.

• Additional relevant patient information, e.g. sweat chloride, lung function, pancreatic status, and Pseudomonas infection rate, associated with each variant/variant combination were included in the evaluation.

Study Using Public Database – An established publicly-maintained database hosted by the academic institution was used to support clinical validity of the test in lieu of clinical trials.

https://www.accessdata.fda.gov/cdrh_docs/reviews/K124006.pdfhttps://www.accessdata.fda.gov/cdrh_docs/reviews/K132750.pdf

https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm509837.pdf

THANK YOU!

Need RWE help for medical devices?CDRHClinicalEvidence@fda.hhs.gov

There are Public-Private Partnerships (PPP) in FDA to enable access to high-quality RWE.

GET INVOLVED – LEARN MORE Michael.Waters@fda.hhs.gov